Suboptimal Immune Recovery

on Antiretroviral TherapyCauses, Consequences, and the Search for Solutions

Richard Jefferys

Treatment Action Group

Nelson Vergel

Program for Wellness Restoration

November 29, 2017

Outline

• Immune system recovery on antiretroviral therapy (ART)

• Factors associated with persistently low CD4 T cell counts despite

HIV viral load suppression

• Studies reporting increased risk of morbidity & mortality

associated with lower CD4 counts on ART

• Candidate therapies for improving immune reconstitution

• Advocacy discussions with the FDA regarding

encouraging the development of candidate therapies

Immune system recovery on ART

• Studies when triple combination ART first became

available showed a consistent pattern of immune recovery

associated with suppression of HIV viral load:

• Rapid increases in numbers of memory CD4 T cells, reflecting both

redistribution from lymph tissues and cell proliferation

• Increased immune responses to pathogens that cause

opportunistic infections (e.g. candida) and routine immunizations

• Decreased over-activation of the immune system

• Slow increase in naïve CD4 T cells from the thymus

E.g. see: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease, Autran et al, Science.

1997 Jul 4;277(5322):112-6.

CD4 gains on ART relate to level at start

From: Incomplete Reconstitution of T Cell Subsets on Combination Antiretroviral Therapy in the AIDS Clinical Trials Group

Protocol 384

Clin Infect Dis. 2009;48(3):350-361. doi:10.1086/595888

Clin Infect Dis | © 2009 by the Infectious Diseases Society of America

A subset of individuals experiences

suboptimal CD4 T cell recovery• No consensus as to how to define suboptimal CD4 T cell recovery (also

referred to as immunological non-response or discordant response)

• A review of published literature found 14 differing definitions in 20 studies

• Suggested criteria have included:

• A CD4 T cell increase of <30% or an absolute count <200 after 6-12 months of ART

• Lack of an increase in the CD4 T cell count to more than 350–500 cells after 4–7

years of HIV suppression by ART

• A rise of less than 50 CD4 T cells after six months of ART in individuals who start

with <350 CD4 T cells

• Estimates are in the range of 15-30% of individuals on ART experiencing

suboptimal immune recovery

Absence of CD4+ T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological

Gaps, and Therapeutic Options, Gazzola et al Clinical Infectious Diseases, Volume 48, Issue 3, 1 February 2009, Pages 328–337

A subset of individuals experiences

suboptimal CD4 T cell recovery

• A combined analysis of two large international cohort studies

(ART-CC & COHERE) looked at individuals who started ART at

<200 CD4 T cells

• Out of 5550 individuals, 835 (15%) did not experience a CD4 T cell

count increase to >200 after three years of HIV suppression by ART

• The phenomenon has been reported in studies from multiple

geographic locations

• The Antiretroviral Therapy in Low Income Countries (ART-LINC)

Collaboration reported 1,260 out of 7,160 (17.6%) individuals

experiencing a lack of CD4 T cell recovery after ~6 months of ART

Estimated outcomes after seven years on

ART based on starting CD4 T cell count

Estimated CD4+ T-cell count outcomes (cells/mm3) had all patients remained on antiretroviral therapy throughout the seven years of follow-up. All estimates

were obtained using inverse probability of censoring weighting (IPCW).

Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection

Lok, Judith J; Bosch, Ronald J; Benson, Constance A; Collier, Ann C; Robbins, Gregory K; Shafer, Robert W; Hughes, Michael D; for the ALLRT team

AIDS 24(12):1867-1876, July 31st, 2010. doi: 10.1097/QAD.0b013e32833adbcf

Estimated % at year 7 Pre-ART ≤200 ≤350 ≤500

>500 0 2 5 351–500 3 3 5

201–350 5 9 45

≤200 11 25 47

Factors associated with suboptimal CD4 T

cell recovery• The most consistently reported associations are with older age and

CD4 T cell count at ART initiation

• Production of new T cells by the bone marrow/thymus is known to decline with

advancing age

• Studies have identified multiple possible contributing mechanisms

• Low T cell production by bone marrow/thymus

• Increased T cell activation and death, potentially caused by co-infections and/or

leaking of normally friendly bacteria from the gut (microbial translocation)

• Scarring damage (fibrosis) in lymph tissue

• Genetic factors (variation in genes related to immunity)

• Anti-CD4 antibodies

Absence of CD4+ T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological

Gaps, and Therapeutic Options, Gazzola et al Clinical Infectious Diseases, Volume 48, Issue 3, 1 February 2009, Pages 328–337

Increased risk of illness and death

• HIV suppression by ART greatly decreases risk of illness

and death

• But most studies have found risk is elevated 2- to 3-fold

among individuals who experience suboptimal CD4 T cell

recovery compared to those with greater increases

• Reviewed in Kelly et al https://doi.org/10.1371/journal.pone.0156099

• In the ART-CC & COHERE study, there were 175 deaths

among the 5550 individuals analyzed over three years:

• 66 (7.9%) of those who did not attain a CD4 count >200 cells, compared to 109

(2.3%) of those who attained a CD4 count >200 cells

Increased risk of illness and death

• Most studies that have assessed risk of AIDS or non-AIDS events have also reported

~2 fold increased risk associated with suboptimal CD4 T cell recovery

Poor CD4 T-cell recovery despite

suppression of viral load

associated with an increased risk

of death, AIDS, cancer, liver

disease, and cardiovascular

events (composite endpoint) in the

Dutch ATHENA HIV cohort

Source: Long-term complications

in patients with poor

immunological recovery despite

virological successful HAART in

Dutch ATHENA cohort

AIDS 26(4):465-474, February

20th, 2012.

Candidate therapies

• Interleukin-2 (IL-2) is a type of immune system messenger protein known as

a cytokine

• IL-2 triggers CD4 T cell proliferation and was studied in two large efficacy

trials in people with HIV: ESPRIT and SILCAAT

• IL-2 was associated with increases in CD4 T cell counts but did not

significantly reduce incidence of illness and death

• Additional studies found IL-2 also failed to improve response to routine

vaccinations in people with HIV on ART

• May have preferentially increased levels of CD4 T cell subsets involved in

immune regulation

• Not all CD4 T cells are created equal, health benefit of an immune-

based intervention must be proven

Candidate therapies

• Interleukin-7 (IL-7) is another cytokine that can increase CD4 T cell numbers via a

different mechanism to IL-2

• Multiple studies in people with HIV on ART indicated potential to promote CD4 T cell

increases

• Some evidence of decreases in inflammation biomarkers

• Possible risk of increase in HIV DNA levels

• Original manufacturer Cytheris had ambitious plans to conduct a large phase III

clinical endpoint trial in HIV+ people with suboptimal immune recovery, but went out

of business in 2015

• The rights to pursue IL-7 as a therapy for HIV-related immune impairment are

reportedly now held by a collaboration involving the French National Agency for

Research on AIDS and Viral Hepatitis (ANRS), but fate currently unclear

• Long-acting IL-7 formulation in development by Korean Company NeoImmuneTech,

but no studies planned in HIV (as yet)

Candidate therapies

• SB-728-T gene therapy

• Extraction of CD4 T cells via apheresis

• Gene modification of the CD4 T cells to remove CCR5 receptor

• Expansion and reinfusion of gene-modified cells

• One of the first trials included a cohort of individuals with suboptimal immune

recovery

• Demonstrated significant CD4 T cell increases and improvements in CD4:CD8 T cell

ratio

• Despite advocacy efforts, biotech manufacturer Sangamo BioSciences has

not shown interest in pursuing development of SB-728-T for this population

Candidate therapies

• A variety of other approaches under study by academic investigators

• Probiotics

• Some reports of anti-inflammatory and other benefits but relatively few published

studies in people with suboptimal immune recovery (ongoing trial of VSL#3 in

Canada)

• Mesenchymal stem cells

• Under study in China and Spain, initial report of CD4 count and anti-inflammatory

benefits in small pilot trial

• Pyridostigmine (acetylcholinesterase inhibitor used to treat myasthenia

gravis)

• Randomized trial ongoing in Mexico, some evidence of CD4 benefit reported in

uncontrolled pilot study

Candidate therapies

• Antifibrotic drug losartan

• Published study reported CD4 T cell benefit from antifibrotic drug added to

ART in the SIV/macaque model

• Two ongoing trials of losartan in HIV+ people on ART with CD4 T cells

<600 (clinicaltrials.gov listings: NCT01852942 and NCT02049307)

• Arabinoxylan rice bran supplementation (BRM4)

• Nutritional supplement being studied in HIV+ people on ART with CD4 T

cells 100-350 at the University of Southern California

Advocacy discussions with FDA

• Meeting held on June 10, 2016

• Notes available online: http://www.treatmentactiongroup.org/basic-

science/FDA-INR-notes

• Possibility raised of using FDA’s orphan drug designation

in the US to encourage development of therapies for

people with suboptimal immune recovery on ART

• Discussion of how to design trials to demonstrate efficacy

US population estimates

• Total HIV+ Population

in the US: 1.3 Million

• 30% Virally

Suppressed = 390,000

people

• ~20% of 390,000 may

have suboptimal

immune recovery =

78,000

• Rough estimate: may

have increased with

recent increases in

proportion of people

with HIV suppression

Predicted yearly additions to population

• The most recent CDC surveillance report states:

• Among persons with an HIV diagnosis during 2015, 21.6% of infections (8,617)

were classified as stage 3 (AIDS) at the time of diagnosis

• This proportion has decreased slightly in recent years: in 2013, it was 23.6% of

infections

• A conservative estimate would be that ~20% of these late-diagnosed

individuals might become INRs (~1,500-2,000 individuals per year)

• This trend should hopefully continue to decline in the future depending on

outreach/education efforts for treatment and prevention

• At the current rate, it is extremely unlikely that there will ever be over

200,000 HIV+ individuals with suboptimal immune reconstitution in the

US (the orphan drug designation patient population maximum)

Advocacy discussions with FDA:

candidate endpoints• Potential ways to assess efficacy (clinical trial endpoints) of

interventions for people with suboptimal immune recovery were

discussed

• Biological markers:

• CD4 T cell count

• CD4:CD8 ratio

• Immune response functionality assessed by routine vaccinations (e.g flu etc.)

• Inflammatory & coagulation biomarkers

• Immune activation biomarkers

• T cell phenotypes

• HIV DNA

Advocacy discussions with FDA:

candidate endpoints• Patient Reported Outcomes (PROs)

• Increasingly used but so far only employed for one HIV-related treatment (Egrifta)

• Frailty Indexes

• Several developed (e.g. the Veterans Aging Cohort Study Index), could be

considered in determining if improvements can result from immune enhancement

therapies, but data lacking on incidence in people with suboptimal immune recovery

• Comorbidities and clinical symptoms

• E.g. diarrhea, fatigue, pain, upper respiratory infections, skin disorders, etc.

However there is also a lack of information on non-serious clinical symptoms in

people with suboptimal immune recovery that needs to be addressed

• FDA open to ideas, but made clear that marketing approval of an

intervention would require some evidence of clinical benefit

Potential next steps

• Follow up webinar with researchers involved in studying

suboptimal immune recovery

• Advocacy statement or article on global need for

candidate interventions

• Continued dialogues with researchers, FDA and industry

• Other ideas?